N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine

Endpoint summary

Description of key information

There are no studies available in which N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2016c), assessment of the toxicokinetic behavior of the substances N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2016c) and taking into account further available information on the present substance.

Oral and dermal absorption of tertiary amines is anticipated because they have low molecular weights. Generally, the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favorable for absorption; molecular weights above 1000 do not favor absorption (ECHA, 2016). In particular the current substance has a molecular weight of 272.47. Furthermore, Lipinski rule of five for the N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine has a score of 0, which indicated the substances to be bioavailable (Danish, QSAR database, 2021). In addition to molecular weight the most useful parameters providing information on the absorption potential are octanol/water partition coefficient (log P) value and the water solubility (ECHA, 2016).

Water-soluble substance will readily dissolve into gastrointestinal fluids. 

In an acute oral toxicity study performed with the target substance the LD50 rat was identified as 2385 mg/kg bw due the presence of mortality.

Dermal absorption is influenced by many factors, e.g, physico-chemical properties of the substance. With regard, to the dermal absorption liquids and substances in solution are taken up more readily than dry particulates. A tiered approach for the estimation of skin absorption has proposed within a risk assessment framework (EC, 2007): Initially, basic physico-chemical information, should be taken into account, i.e. molecular mass and lipophilicity (log P). Following, skin absorption is generally predicted unless molecular mass is above 500 and log P is outside the range [-1, 4], in which case a value of 10% skin absorption is chosen.  Furthermore, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Thus, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Between 1-100 mg/L absorption is anticipated to be low to moderate and between 100-10,000 mg/L moderate to high.  However, if the water solubility is above 10,000 mg/L and log P values below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low.

N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine is completely soluble in water and has a log P value of 0. Thus, the present substance has the potential to be well absorbed via dermal route.

In an acute dermal toxicity study performed with N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine the lowest LD50 (females) is 1171 mg/kg bw. The substance was very irritating, corrosive and systemically toxic when applied to the skin of rabbits. Local effects were not reversible within two weeks.

Signs of systemic toxicity including hematuria, decreased activity, ataxia and dyspnea were also observed. Liver discoloration and hemorrhagic changes in the stomach, lungs and kidneys were observed macroscopically and dermal necrosis and subcutaneous hemorrhages, edema and inflammation were observed microscopically in rabbits treated with the target substance.

Based on these considerations we can predict that signs of systemic toxicity indicate that absorption has occurred for the substance of interest.

With regard the absorption inhalation route the important parameters are: vapor pressure, hydrolysis test, and log P. Vapor pressure is a parameter for a substance to be available for inhalation as a vapor. As a general guide, highly volatile substances are those with a vapor pressure greater than 25 KPa (or a boiling point below 50°C). Substances with low volatility have a vapor pressure of less than 0.5 KPa (or a boiling point above 150°C). Both target and source substances have a low volatility. Moderate log P values (between -1 and 4) are favorable for absorption directly across the respiratory tract epithelium by passive diffusion. This is the case for the target and source substances as well.

The available Inhalation toxicity data of N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine did not show any adverse effects.

Hydrolysis data are not available for target and source substances. However, tertiary alkylamine are well known to be hydrolytically stable. 

Based on the physicochemical properties of the substance under evaluation data on acute inhalation toxicity of the target and source substances, the absorption via the lung is expected.

ECHA guidance 2016 states that if the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamineresulted to be corrosive to skin.

Taken all together, on the basis of the above consideration we can predict the N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine to be absorbed via dermal route.

Overall, it can be concluded that, target and source substances are expected to be well absorbed in the respiratory and gastro-intestinal tracts, which may be a route of low-level chronic exposure.

Distribution within the body through the circulatory system depends on the molecular weight, the and water solubility. If general, the smaller the molecule, the wider is the distribution. Small water-soluble molecules and ions will diffuse through aquaeous channels and pores. The water solubility of N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine favors extensive and possibly systemic distribution via the circulatory system. If the molecule has a log P> 0 it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

As explained in Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2016c) lipophilic substances have the potential to accumulate within the body depending on the conditions of the exposure. If the dosing interval is shorter that the 4 times the whole half-life of the substance, then there is the potential for the substance to accumulate. It is generally the case that the substances with the log P values have long biological half-lives. Based on these considerations, daily exposure to a substance with a log P value of around 4 or higher may results in a build-up of that substance within the body. Substances with a log P values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patters normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

Highly lipophilic substances (log P between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systematically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. Based on the fact that target and source substances have log Pow lower than 4 then a low bioaccumulation potential due to for N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine.

Metabolism of the tertiary aliphatic amines is generally well understood and mediated primarily by cytochrome P-450 and MFAO, leading to alpha-C oxidation and N-oxidation, leading to rapid clearance (Rose & Castagnoli, 1983).

There is a commonality in the metabolism of the tertiary amines. N-oxide formation and excretion of both freebase and N-form, with some dealkylation, appears to be the major route of excretion for the lower molecular weight tertiary amines.

Skin metabolism simulator and rat S9 metabolism simulator OECD QSAR toolbox 4.4 shows for N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine the generation of the same kind of metabolites such as aliphatic amine (secondary and tertiary amines), aldehydes, ammonia and formic acid and formats aliphatic acids among others.

The major routes of excretion for substances from the systemic circulation are the urine and/or the feces. The excretion processes involved in the kidney are passive glomerular filtration through membranes pores and active tubular secretion via carrier process. Substances that are excreted in the urine tend to be water-soluble and of low molecular weight (below 300 in rat, mostly anionic and cationic compounds) and generally, they are conjugated metabolites (e.g. glucoronides, sulphates, glycine conjugates) from Phase II biotransformation. Most of them will have been filtered out of the blood by the kidneys through a small amount may enter the urine directly by passive diffusion. In the rat, molecules that are excreted in the bile are amphipathic (containing both polar and non-polar regions), hydrophobic/strongly polar and have high molecular weight. In general, in rats for organic cations with a molecular wight below 300 it is unlikely that more than 5-10% will be excreted in the bile. Talking all these considerations together and taking into account that the target and source substances have a molecular weight below 300 and high-water solubility, we can conclude that the N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine is excreted mainly via urine.

 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100